tbuckley/cabot-search huggingface dataset:
Long-term effectiveness and persistence of ustekinumab and TNF inhibitors in patients with psoriatic arthritis: final 3-year results from the PsABio real-world study
Authors: Laure Gossec, Stefan Siebert, Paul Bergmans, Kurt de Vlam, Elisa Gremese, Beatriz Joven-Ibáñez, Tatiana V Korotaeva, Frederic Lavie, Wim Noël, Michael T Nurmohamed, Petros P Sfikakis, Mohamed Sharaf, Elke Theander, Josef S Smolen
Journal: Annals of the Rheumatic Diseases (2022)

To evaluate real-world persistence and effectiveness of the IL-12/23 inhibitor, ustekinumab or a tumour necrosis factor inhibitor (TNFi) for psoriatic arthritis over 3 years.PsABio (NCT02627768), a prospective, observational study, followed patients with PsA prescribed first-line to third-line ustekinumab or a TNFi. Persistence and effectiveness (achievement of clinical Disease Activity for PSA (cDAPSA) low disease activity (LDA)/remission and minimal disease activity/very LDA (MDA/VLDA)) were assessed every 6 months. Safety data were collected over 3 years. Analyses to compare the modes of action were adjusted on baseline differences by propensity scores (PS).In 895 patients (mean age 49.8 years, 44.7% males), at 3 years, the proportion of patients still on their initial treatments was similar with ustekinumab (49.9%) and TNFi (47.8%). No difference was seen in the risk of stopping/switching; PS-adjusted hazard ratio (95% CI) for stopping/switching ustekinumab versus TNFi was 0.87 (0.68 to 1.11). In the overall population, cDAPSA LDA/remission was achieved in 58.6%/31.4% ustekinumab-treated and 69.8%/45.0% TNFi-treated patients; PS-adjusted ORs (95% CI) were 0.89 (0.63 to 1.26) for cDAPSA LDA; 0.72 (0.50 to 1.05) for remission. MDA/VLDA was achieved in 41.4%/19.2% of ustekinumab-treated and 54.2%/26.9% of TNFi-treated patients with overlapping PS-adjusted ORs. A greater percentage of TNFi-treated patients achieved effectiveness outcomes. Both treatments exhibited good long-term safety profiles, although ustekinumab-treated patients had a lower rate of adverse events (AEs) versus TNFi.At 3 years, there was generally comparable persistence after ustekinumab or TNFi treatment, but AE rates were lower with ustekinumab.
Concussion increases within-player injury risk in male professional rugby union
Authors: Isabel S Moore, Charlotte Leah Bitchell, Danielle Vicary, James Rafferty, Ben Charles Robson, Prabhat Mathema
Journal: British Journal of Sports Medicine (2022)

To assess within-player change in injury risk and between-player subsequent injury risk associated with concussive and common non-concussive injuries in professional rugby union.
The c-MYC-WDR43 signalling axis promotes chemoresistance and tumour growth in colorectal cancer by inhibiting p53 activity
Authors: Yuqin Di, Xiaoqian Jing, Kunhua Hu, Xiangqiong Wen, Lvlan Ye, Xiang Zhang, Jiale Qin, Jinning Ye, Run Lin, Ziyang Wang, Weiling He
Journal: Drug Resistance Updates (2022)
Potential binding modes of the gut bacterial metabolite, 5-hydroxyindole, to the intestinal L-type calcium channels and its impact on the microbiota in rats
Authors: Barbora Waclawiková, Paulo Cesar Telles de Souza, Markus Schwalbe, Constantinos G. Neochoritis, Warner Hoornenborg, Sieger A. Nelemans, Siewert J. Marrink, Sahar El Aidy
Journal: Gut Microbes (2022)

Intestinal microbiota and microbiota-derived metabolites play a key role in regulating the host physiology. Recently, we have identified a gut-bacterial metabolite, namely 5-hydroxyindole, as a potent stimulant of intestinal motility via its modulation of L-type voltage-gated calcium channels located on the intestinal smooth muscle cells. Dysregulation of L-type voltage-gated calcium channels is associated with various gastrointestinal motility disorders, including constipation, making L-type voltage-gated calcium channels an important target for drug development. Nonetheless, the majority of currently available drugs are associated with alteration of the gut microbiota. Using 16S rRNA sequencing this study shows that, when administered orally, 5-hydroxyindole has only marginal effects on the rat cecal microbiota. Molecular dynamics simulations propose potential-binding pockets of 5-hydroxyindole in the α1 subunit of the L-type voltage-gated calcium channels and when its stimulatory effect on the rat colonic contractility was compared to 16 different analogues, ex-vivo, 5-hydroxyindole stood as the most potent enhancer of the intestinal contractility. Overall, the present findings imply a potential role of microbiota-derived metabolites as candidate therapeutics for targeted treatment of slow intestinal motility-related disorders including constipation.
Spatial omics technologies at multimodal and single cell/subcellular level
Authors: Jiwoon Park, Junbum Kim, Tyler Lewy, Charles M. Rice, Olivier Elemento, André F. Rendeiro, Christopher E. Mason
Journal: Genome biology (2022)

Abstract Spatial omics technologies enable a deeper understanding of cellular organizations and interactions within a tissue of interest. These assays can identify specific compartments or regions in a tissue with differential transcript or protein abundance, delineate their interactions, and complement other methods in defining cellular phenotypes. A variety of spatial methodologies are being developed and commercialized; however, these techniques differ in spatial resolution, multiplexing capability, scale/throughput, and coverage. Here, we review the current and prospective landscape of single cell to subcellular resolution spatial omics technologies and analysis tools to provide a comprehensive picture for both research and clinical applications.
Ultrasound-triggered piezocatalytic composite hydrogels for promoting bacterial-infected wound healing
Authors: Dun Liu, Lei Li, Ben-Long Shi, Bo Shi, Ming-Ding Li, Yong Qiu, Di Zhao, Qun-Dong Shen, Ze-Zhang Zhu
Journal: Bioactive Materials (2022)

Wound healing has become one of the basic issues faced by the medical community because of the susceptibility of skin wounds to bacterial infection. As such, it is highly desired to design a nanocomposite hydrogel with excellent antibacterial activity to achieve high wound closure effectiveness. Here, based on ultrasound-triggered piezocatalytic therapy, a multifunctional hydrogel is designed to promote bacteria-infected wound healing. Under ultrasonic vibration, the surface of barium titanate (BaTiO3, BT) nanoparticles embedded in the hydrogel rapidly generate reactive oxygen species (ROS) owing to the established strong built-in electric field, endowing the hydrogel with superior antibacterial efficacy. This modality shows intriguing advantages over conventional photodynamic therapy, such as prominent soft tissue penetration ability and the avoidance of serious skin phototoxicity after systemic administration of photosensitizers. Moreover, the hydrogel based on N-[tris(hydroxymethyl)methyl]acrylamide (THM), N-(3-aminopropyl)methacrylamide hydrochloride (APMH) and oxidized hyaluronic acid (OHA) exhibits outstanding self-healing and bioadhesive properties able to accelerate full-thickness skin wound healing. Notably, compared with the widely reported mussel-inspired adhesive hydrogels, OHA/THM-APMH hydrogel due to the multiple hydrogen bonds from unique tri-hydroxyl structure overcomes the shortage that catechol groups are easily oxidized, giving it long-term and repeatable adhesion performance. Importantly, this hybrid hydrogel confines BT nanoparticles to wound area and locally induced piezoelectric catalysis under ultrasound to eradicate bacteria, markedly improving the therapeutic biosafety and exhibits great potential for harmless treatment of bacteria-infected tissues.
Management of patients with lower-risk myelodysplastic syndromes
Authors: Andrew M. Brunner, Heather A. Leitch, Arjan A. van de Loosdrecht, Nicolas Bonadies
Journal: Blood Cancer Journal (2022)

Abstract Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders characterized by ineffective hematopoiesis with abnormal blood cell development (dysplasia) leading to cytopenias and an increased risk for progression to acute myeloid leukemia (AML). Patients with MDS can generally be classified as lower- (LR-MDS) or higher-risk (HR-MDS). As treatment goals for patients with LR-MDS and those with HR-MDS differ significantly, appropriate diagnosis, classification, and follow-up are critical for correct disease management. In this review, we focus on the diagnosis, prognosis, and treatment options, as well as the prediction of the disease course and monitoring of treatment response in patients with LR-MDS. We discuss how next-generation sequencing, increasing knowledge on mechanisms of MDS pathogenesis, and novel therapies may change the current treatment landscape in LR-MDS and why structured assessments of responses, toxicities, and patient-reported outcomes should be incorporated into routine clinical practice.
Tobacco Smoking-Related Mutational Signatures in Classifying Smoking-Associated and Nonsmoking-Associated NSCLC
Authors: Sophie M. Ernst, Joanne M. Mankor, Job van Riet, Jan H. von der Thüsen, Hendrikus J. Dubbink, Joachim G.J.V. Aerts, Adrianus J. de Langen, Egbert F. Smit, Anne-Marie C. Dingemans, Kim Monkhorst
Journal: Journal of Thoracic Oncology (2022)
WITHDRAWN: DUSP1 overexpression attenuates septic cardiomyopathy through reducing VCP phosphorylation and normalizing mitochondrial quality control
Authors: Ying Tan, Dan Xi, Chen Cai, Xiaoqing Jiang, Shanshan Chen, Ruiying Hu, Ting Xin, Yukun Li, Shiyuan Wang, Xing Chang, Hao Zhou
Journal: Acta Pharmaceutica Sinica B (2022)
Epidemiology of alopecia areata in Hispanic/Latinx patients
Authors: Celine H. Phong, Amy J. McMichael, Natasha Atanaskova Mesinkovska
Journal: Journal of the American Academy of Dermatology (2022)

To the Editor: A recent study by Feaster and McMichael examined the epidemiology of alopecia areata (AA) in Black patients.1 A similar unmet need exists to describe the characteristics of AA in Hispanic/Latinx (H/L) patients, the prevalent majority in California (39.4%, US Census Bureau 2021).
Defining the serum proteomic signature of hepatic steatosis, inflammation, ballooning and fibrosis in non-alcoholic fatty liver disease
Authors: Arun J Sanyal, Stephen A Williams, Joel E Lavine, Brent A Neuschwander-Tetri, Leigh Alexander, Rachel Ostroff, Hannah Biegel, Kris V Kowdley, Naga Chalasani, Srinivasan Dasarathy, Anna Mae Diehl, Rohit Loomba, Bilal Hameed, Cynthia Behling, David E Kleiner, Saul J Karpen, Jessica Williams, Yi Jia, Katherine P Yates, James Tonascia
Journal: Journal of Hepatology (2022)
Single-cell microglial transcriptomics during demyelination defines a microglial state required for lytic carcass clearance
Authors: Sameera Zia, Brady P. Hammond, Martin Zirngibl, Anastasia Sizov, Charbel S. Baaklini, Sharmistha P. Panda, Madelene F. S. Ho, Kelly V. Lee, Apurba Mainali, Mena K. Burr, Sioned Williams, Andrew V. Caprariello, Christopher Power, Thomas Simmen, Bradley J. Kerr, Jason R. Plemel
Journal: Molecular Neurodegeneration (2022)

Abstract Background Microglia regulate the response to injury and disease in the brain and spinal cord. In white matter diseases microglia may cause demyelination. However, how microglia respond and regulate demyelination is not fully understood. Methods To understand how microglia respond during demyelination, we fed mice cuprizone—a potent demyelinating agent—and assessed the dynamics of genetically fate-mapped microglia. We then used single-cell RNA sequencing to identify and track the microglial subpopulations that arise during demyelination. To understand how microglia contribute to the clearance of dead oligodendrocytes, we ablated microglia starting at the peak of cuprizone-induced cell death and used the viability dye acridine orange to monitor apoptotic and lytic cell morphologies after microglial ablation. Lastly, we treated serum-free primary microglial cultures to model distinct aspects of cuprizone-induced demyelination and assessed the response. Results The cuprizone diet generated a robust microglial response by week 4 of the diet. Single-cell RNA sequencing at this time point revealed the presence of several cuprizone-associated microglia (CAM) clusters. These clusters expressed a transcriptomic signature indicative of cytokine regulation and reactive oxygen species production with altered lysosomal and metabolic changes consistent with ongoing phagocytosis. Using acridine orange to monitor apoptotic and lytic cell death after microglial ablation, we found that microglia preferentially phagocytose lytic carcasses. In culture, microglia exposed to lytic carcasses partially recapitulated the CAM state, suggesting that phagocytosis contributes to this distinct microglial state during cuprizone demyelination. Conclusions Microglia serve multiple roles during demyelination, yet their transcriptomic state resembles other neurodegenerative conditions. The phagocytosis of cellular debris is likely a universal cause for a common neurodegenerative microglial state.
Structural variant analysis of a cancer reference cell line sample using multiple sequencing technologies
Authors: Keyur Talsania, Tsai-wei Shen, Xiongfong Chen, Erich Jaeger, Zhipan Li, Zhong Chen, Wanqiu Chen, Bao Tran, Rebecca Kusko, Limin Wang, Andy Wing Chun Pang, Zhaowei Yang, Sulbha Choudhari, Michael Colgan, Li Tai Fang, Andrew Carroll, Jyoti Shetty, Yuliya Kriga, Oksana German, Tatyana Smirnova, Tiantain Liu, Jing Li, Ben Kellman, Karl Hong, Alex R. Hastie, Aparna Natarajan, Ali Moshrefi, Anastasiya Granat, Tiffany Truong, Robin Bombardi, Veronnica Mankinen, Daoud Meerzaman, Christopher E. Mason, Jack Collins, Eric Stahlberg, Chunlin Xiao, Charles Wang, Wenming Xiao, Yongmei Zhao
Journal: Genome biology (2022)

Abstract Background The cancer genome is commonly altered with thousands of structural rearrangements including insertions, deletions, translocation, inversions, duplications, and copy number variations. Thus, structural variant (SV) characterization plays a paramount role in cancer target identification, oncology diagnostics, and personalized medicine. As part of the SEQC2 Consortium effort, the present study established and evaluated a consensus SV call set using a breast cancer reference cell line and matched normal control derived from the same donor, which were used in our companion benchmarking studies as reference samples. Results We systematically investigated somatic SVs in the reference cancer cell line by comparing to a matched normal cell line using multiple NGS platforms including Illumina short-read, 10X Genomics linked reads, PacBio long reads, Oxford Nanopore long reads, and high-throughput chromosome conformation capture (Hi-C). We established a consensus SV call set of a total of 1788 SVs including 717 deletions, 230 duplications, 551 insertions, 133 inversions, 146 translocations, and 11 breakends for the reference cancer cell line. To independently evaluate and cross-validate the accuracy of our consensus SV call set, we used orthogonal methods including PCR-based validation, Affymetrix arrays, Bionano optical mapping, and identification of fusion genes detected from RNA-seq. We evaluated the strengths and weaknesses of each NGS technology for SV determination, and our findings provide an actionable guide to improve cancer genome SV detection sensitivity and accuracy. Conclusions A high-confidence consensus SV call set was established for the reference cancer cell line. A large subset of the variants identified was validated by multiple orthogonal methods.
High-grade B-cell lymphoma (HGBL)-NOS is clinicopathologically and genetically more similar to DLBCL/HGBL-DH than DLBCL
Authors: Shaoying Li, Lianqun Qiu, Jie Xu, Pei Lin, Chi Young Ok, Guilin Tang, Timothy J. McDonnell, M. James You, Mahsa Khanlari, Roberto N. Miranda, L. Jeffrey Medeiros
Journal: Leukemia (2022)
Bioengineering a miniaturized in vitro 3D myotube contraction monitoring chip to model muscular dystrophies
Authors: Nicolas Rose, Berenice Estrada Chavez, Surabhi Sonam, Thao Nguyen, Gianluca Grenci, Anne Bigot, Antoine Muchir, Benoît Ladoux, Bruno Cadot, Fabien Le Grand, Léa Trichet
Journal: Biomaterials (2022)
A pro B cell population forms the apex of the leukemic hierarchy in Hoxa9/Meis1-dependent AML
Authors: Anna Lieske, Eric Agyeman-Duah, Anton Selich, Nicole Dörpmund, Steven R. Talbot, Axel Schambach, Tobias Maetzig
Journal: Leukemia (2022)

Relapse is a major challenge to therapeutic success in acute myeloid leukemia (AML) and can be partly associated with heterogeneous leukemic stem cell (LSC) properties. In the murine Hoxa9/Meis1-dependent (H9M) AML model, LSC potential lies in three defined immunophenotypes, including Lin-cKit+ progenitor cells (Lin-), Gr1+CD11b+cKit+ myeloid cells, and lymphoid cells (Lym+). Previous reports demonstrated their interconversion and distinct drug sensitivities. In contrast, we here show that H9M AML is hierarchically organized. We, therefore, tracked the developmental potential of LSC phenotypes. This unexpectedly revealed a substantial fraction of Lin- LSCs that failed to regenerate Lym+ LSCs, and that harbored reduced leukemogenic potential. However, Lin- LSCs capable of producing Lym+ LSCs as well as Lym+ LSCs triggered rapid disease development suggestive of their high relapse-driving potential. Transcriptional analyses revealed that B lymphoid master regulators, including Sox4 and Bach2, correlated with Lym+ LSC development and presumably aggressive disease. Lentiviral overexpression of Sox4 and Bach2 induced dedifferentiation of H9M cells towards a lineage-negative state in vitro as the first step of lineage conversion. This work suggests that the potency to initiate a partial B lymphoid primed transcriptional program as present in infant AML correlates with aggressive disease and governs the H9M LSC hierarchy.
Short- and long-term effects of an electronic medication management system on paediatric prescribing errors
Authors: Johanna I. Westbrook, Ling Li, Magdalena Z. Raban, Virginia Mumford, Tim Badgery-Parker, Peter Gates, Erin Fitzpatrick, Alison Merchant, Amanda Woods, Melissa Baysari, Cheryl McCullagh, Ric Day, Madlen Gazarian, Michael Dickinson, Karla Seaman, Lucciano Dalla-Pozza, Geoffrey Ambler, Peter Barclay, Alan Gardo, Tracey O’Brien, Draga Barbaric, Les White
Journal: npj Digital Medicine (2022)

Electronic medication management (eMM) systems are designed to improve safety, but there is little evidence of their effectiveness in paediatrics. This study assesses the short-term (first 70 days of eMM use) and long-term (one-year) effectiveness of an eMM system to reduce prescribing errors, and their potential and actual harm. We use a stepped-wedge cluster randomised controlled trial (SWCRCT) at a paediatric referral hospital, with eight clusters randomised for eMM implementation. We assess long-term effects from an additional random sample of medication orders one-year post-eMM. In the SWCRCT, errors that are potential adverse drug events (ADEs) are assessed for actual harm. The study comprises 35,260 medication orders for 4821 patients. Results show no significant change in overall prescribing error rates in the first 70 days of eMM use (incident rate ratio [IRR] 1.05 [95%CI 0.92-1.21], but a 62% increase (IRR 1.62 [95%CI 1.28-2.04]) in potential ADEs suggesting immediate risks to safety. One-year post-eMM, errors decline by 36% (IRR 0.64 [95%CI 0.56-0.72]) and high-risk medication errors decrease by 33% (IRR 0.67 [95%CI 0.51-0.88]) compared to pre-eMM. In all periods, dose error rates are more than double that of other error types. Few errors are associated with actual harm, but 71% [95%CI 50-86%] of patients with harm experienced a dose error. In the short-term, eMM implementation shows no improvement in error rates, and an increase in some errors. A year after eMM error rates significantly decline suggesting long-term benefits. eMM optimisation should focus on reducing dose errors due to their high frequency and capacity to cause harm.
Pegcetacoplan: A Review in Paroxysmal Nocturnal Haemoglobinuria
Authors: Young-A Heo
Journal: Drugs (2022)

Subcutaneous pegcetacoplan (EMPAVELI® in the USA and ASPAVELI® in the EU) is the first complement component 3 (C3) inhibitor approved for the treatment of adults with paroxysmal nocturnal haemoglobinuria (PNH) in the USA, and in adults with PNH who are anaemic after ≥ 3 months of treatment with a C5 inhibitor in the EU. In the phase III PRINCE trial in adults with PNH who were anaemic and naïve to a complement inhibitor therapy, pegcetacoplan was superior to the control group (supportive care, excluding complement inhibitors) in achieving haemoglobin stabilization and reducing lactate dehydrogenase levels. Similarly, in the phase III PEGASUS trial in adults with PNH who had a haemoglobin level < 10.5 g/dL despite eculizumab therapy, pegcetacoplan was superior to eculizumab in improving haemoglobin levels. In both trials, pegcetacoplan also improved other clinical and haematological parameters of haemolysis, as well as quality of life (QOL) outcomes. Clinical benefits of pegcetacoplan were sustained for up to 48 weeks of treatment. Pegcetacoplan was generally well tolerated in patients with PNH, with its tolerability profile being similar in patients previously treated with eculizumab and in complement inhibitor-naïve patients. Long-term data would be beneficial to further support the safety profile of pegcetacoplan. Current evidence indicates that pegcetacoplan is a valuable treatment option for adults with PNH. Paroxysmal nocturnal haemoglobinuria (PNH) is a rare haematological disorder that is characterized by complement-mediated haemolysis, fatigue and thrombotic events. Complement component 5 (C5) inhibitors eculizumab and ravulizumab have demonstrated substantial efficacy in reducing intravascular haemolysis and improving quality of life (QOL) in patients with PNH; however, many patients continue to exhibit anaemia and require transfusions because of uncontrolled extravascular haemolysis. Subcutaneous pegcetacoplan (EMPAVELI® in the USA and ASPAVELI® in the EU) is the first C3 inhibitor approved in the USA and EU for the treatment of PNH. Pegcetacoplan targets C3 in the complement cascade, upstream of C5, thereby providing control over both intravascular and extravascular haemolysis. Pegcetacoplan was superior to supportive care in improving clinical and haematological outcomes in patients with PNH who were naïve to a complement inhibitor therapy. Similarly, pegcetacoplan was superior to eculizumab in improving clinical and haematological outcomes in patients with uncontrolled PNH despite eculizumab therapy. Pegcetacoplan also improved QOL and fatigue symptoms. Pegcetacoplan was generally well tolerated, with most adverse events being mild to moderate in severity. Current evidence indicates that pegcetacoplan is a valuable treatment option for adults with PNH.
Activation of a Latent Epitope Causing Differential Binding of Antineutrophil Cytoplasmic Antibodies to Proteinase 3
Authors: Marta Casal Moura, Gwen E. Thompson, Darlene R. Nelson, Lynn A. Fussner, Amber M. Hummel, Dieter E. Jenne, Daniel Emerling, Fernando C. Fervenza, Cees G. M. Kallenberg, Carol A. Langford, W. Joseph McCune, Peter A. Merkel, Paul A. Monach, Philip Seo, Robert F. Spiera, E. William St. Clair, Steven R. Ytterberg, John H. Stone, William H. Robinson, Ulrich Specks
Journal: Arthritis & Rheumatology (2022)

Proteinase 3 (PR3) is the major antigen for antineutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3-targeting ANCAs (PR3-ANCAs) recognize different epitopes on PR3. This study was undertaken to study the effect of mutations on PR3 antigenicity.